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Fulltext Human soluble CD39 displays substrate inhibition in a substrate-specific manner

Vadlamani VMK, Gunasinghe KKJ, Chee XW, Rahman T, Harper MT

Sci Rep, 2023 Jun 02;13(1):8958.
PMID: 37268726 DOI: 10.1038/s41598-023-36257-3

CD39 (ectonucleoside triphosphate diphosphohydrolase-1; ENTPD1) metabolizes extracellular ATP and ADP to AMP. AMP is subsequently metabolized by CD79 to adenosine. CD39 activity is therefore a key regulator of purinergic signalling in cancer, thrombosis, and autoimmune diseases. In this study we demonstrate that soluble, recombinant CD39 shows substrate inhibition with ADP or ATP as the substrate. Although CD39 activity initially increased with increasing substrate concentration, at high concentrations of ATP or ADP, CD39 activity was markedly reduced. Although the reaction product, AMP, inhibits CD39 activity, insufficient AMP was generated under our conditions to account for the substrate inhibition seen. In contrast, inhibition was not seen with UDP or UTP as substrates. 2-methylthio-ADP also showed no substrate inhibition, indicating the nucleotide base is an important determinant of substrate inhibition. Molecular dynamics simulations revealed that ADP can undergo conformational rearrangements within the CD39 active site that were not seen with UDP or 2-methylthio-ADP. Appreciating the existence of substrate inhibition of CD39 will help the interpretation of studies of CD39 activity, including investigations into drugs that modulate CD39 activity.

Matched MeSH terms: Adenosine Triphosphate/metabolism
Mechanisms of cataractogenesis in the presence of magnesium deficiency

Agarwal R, Iezhitsa IN, Agarwal P, Spasov AA

Magnes Res, 2013 Jan-Feb;26(1):2-8.
PMID: 23708888 DOI: 10.1684/mrh.2013.0336

Senile cataract is the most common cause of bilateral blindness and results from the loss of transparency of the lens. Maintenance of the unique tissue architecture of the lens is vital for keeping the lens transparent. Membrane transport mechanisms utilizing several magnesium (Mg)-dependent ATPases, play an important role in maintaining lens homeostasis. Therefore, in Mg-deficiency states, ATPase dysfunctions lead to intracellular depletion of K(+) and accumulation of Na(+) and Ca(2+). High intracellular Ca(2+) causes activation of the enzyme calpain II, which leads to the denaturation of crystallin, the soluble lens protein required for maintaining the transparency of the lens. Mg deficiency also interferes with ATPase functions by causing cellular ATP depletion. Furthermore, Mg deficiency enhances lenticular oxidative stress by increased production of free radicals and depletion of antioxidant defenses. Therefore, Mg supplementation may be of therapeutic value in preventing the onset and progression of cataracts in conditions associated with Mg deficiency.

Matched MeSH terms: Adenosine Triphosphate/deficiency
Fulltext More than a drug target: Purinergic signalling as a source for diagnostic tools in epilepsy

Wong ZW, Engel T

Neuropharmacology, 2023 Jan 01;222:109303.
PMID: 36309046 DOI: 10.1016/j.neuropharm.2022.109303

Epilepsy is one of the most common and disabling chronic neurological diseases affecting people of all ages. Major challenges of epilepsy management include the persistently high percentage of drug-refractoriness among patients, the absence of disease-modifying treatments, and its diagnosis and prognosis. To date, long-term video-electroencephalogram (EEG) recordings remain the gold standard for an epilepsy diagnosis. However, this is very costly, has low throughput, and in some instances has very limited availability. Therefore, much effort is put into the search for non-invasive diagnostic tests. Purinergic signalling, via extracellularly released adenosine triphosphate (ATP), is gaining increasing traction as a therapeutic strategy for epilepsy treatment which is supported by evidence from both experimental models and patients. This includes in particular the ionotropic P2X7 receptor. Besides that, other components from the ATPergic signalling cascade such as the metabotropic P2Y receptors (e.g., P2Y1 receptor) and ATP-release channels (e.g., pannexin-1), have also been shown to contribute to seizures and epilepsy. In addition to the therapeutic potential of purinergic signalling, emerging evidence has also shown its potential as a diagnostic tool. Following seizures and epilepsy, the concentration of purines in the blood and the expression of different compounds of the purinergic signalling cascade are significantly altered. Herein, this review will provide a detailed discussion of recent findings on the diagnostic potential of purinergic signalling for epilepsy management and the prospect of translating it for clinical application. This article is part of the Special Issue on 'Purinergic Signaling: 50 years'.

Matched MeSH terms: Adenosine Triphosphate/metabolism
Fulltext ATP-binding cassette (ABC) transporters: structures and roles in bacterial pathogenesis

How SS, Nathan S, Lam SD, Chieng S

J Zhejiang Univ Sci B, 2024 Oct 21;26(1):58-75.
PMID: 39815611 DOI: 10.1631/jzus.B2300641

Adenosine triphosphate (ATP)-binding cassette (ABC) transporter systems are divided into importers and exporters that facilitate the movement of diverse substrate molecules across the lipid bilayer, against the concentration gradient. These transporters comprise two highly conserved nucleotide-binding domains (NBDs) and two transmembrane domains (TMDs). Unlike ABC exporters, prokaryotic ABC importers require an additional substrate-binding protein (SBP) as a recognition site for specific substrate translocation. The discovery of a large number of ABC systems in bacterial pathogens revealed that these transporters are crucial for the establishment of bacterial infections. The existing literature has highlighted the roles of ABC transporters in bacterial growth, pathogenesis, and virulence. These roles include importing essential nutrients required for a variety of cellular processes and exporting outer membrane-associated virulence factors and antimicrobial substances. This review outlines the general structures and classification of ABC systems to provide a comprehensive view of the activities and roles of ABC transporters associated with bacterial virulence and pathogenesis during infection.

Matched MeSH terms: Adenosine Triphosphate/metabolism
Fulltext Connexin therapeutics: blocking connexin hemichannel pores is distinct from blocking pannexin channels or gap junctions

Acosta ML, Mat Nor MN, Guo CX, Mugisho OO, Coutinho FP, Rupenthal ID, et al.

Neural Regen Res, 2021 Mar;16(3):482-488.
PMID: 32985469 DOI: 10.4103/1673-5374.290097

Compounds that block the function of connexin and pannexin protein channels have been suggested to be valuable therapeutics for a range of diseases. Some of these compounds are now in clinical trials, but for many of them, the literature is inconclusive about the molecular effect on the tissue, despite evidence of functional recovery. Blocking the different channel types has distinct physiological and pathological implications and this review describes current knowledge of connexin and pannexin protein channels, their function as channels and possible mechanisms of the channel block effect for the latest therapeutic compounds. We summarize the evidence implicating pannexins and connexins in disease, considering their homeostatic versus pathological roles, their contribution to excesive ATP release linked to disease onset and progression.

Matched MeSH terms: Adenosine Triphosphate
Fulltext A randomised approach for enumerating migrated cells in a transwell migration assay

Kanesan, Livashini, Siti Sarah Omar Zaki, Vidyadaran, Sharmili

Malaysian Journal of Medicine and Health Sciences, 2018;14(103):50-53.
MyJurnal

The transwell migration assay is commonly used for assessing cell migration. It involves the enumeration of cells that
have migrated across a pore-containing membrane. We describe a randomised approach to quantifying migrated
cells and compare it to a conventional full cell count. We used ATP as a chemoattractant and automatic cell quantification performed on all fields (Full count; FC) or 10 randomly selected fields (Randomised count; RC). The two
methods were compared by evaluating standard deviations (SD), coefficient of variation (CV) and using the Bland-Altman analysis. The dispersion of data is higher with the RC approach (3.77-6.66% CV for control; 3.89-4.48% CV
for ATP-treated wells) compared to FC (0.27-0.46% CV for control; 0.05-0.09% CV for ATP-treated wells), but are
acceptable considering that the number of migrated cells are in the thousands. Both methods verified that an ATP
migration assay for BV2 microglia was established, demonstrating that the RC approach is reliable and comparable
to a full count.

Matched MeSH terms: Adenosine Triphosphate
Fulltext Elevated-Temperature Performance, Combustibility and Fire Propagation Index of Fly Ash-Metakaolin Blend Geopolymers with Addition of Monoaluminium Phosphate (MAP) and Aluminum Dihydrogen Triphosphate (ATP)

Zulkifly K, Cheng-Yong H, Yun-Ming L, Bayuaji R, Abdullah MMAB, Ahmad SB, et al.

Materials (Basel), 2021 Apr 15;14(8).
PMID: 33920865 DOI: 10.3390/ma14081973

Thermal performance, combustibility, and fire propagation of fly ash-metakaolin (FA-MK) blended geopolymer with the addition of aluminum triphosphate, ATP (Al(H2PO4)3), and monoaluminium phosphate, MAP (AlPO4) were evaluated in this paper. To prepare the geopolymer mix, fly ash and metakaolin with a ratio of 1:1 were added with ATP and MAP in a range of 0-3% by weight. The fire/heat resistance was evaluated by comparing the residual compressive strengths after the elevated temperature exposure. Besides, combustibility and fire propagation tests were conducted to examine the thermal performance and the applicability of the geopolymers as passive fire protection. Experimental results revealed that the blended geopolymers with 1 wt.% of ATP and MAP exhibited higher compressive strength and denser geopolymer matrix than control geopolymers. The effect of ATP and MAP addition was more obvious in unheated geopolymer and little improvement was observed for geopolymer subjected to elevated temperature. ATP and MAP at 3 wt.% did not help in enhancing the elevated-temperature performance of blended geopolymers. Even so, all blended geopolymers, regardless of the addition of ATP and MAP, were regarded as the noncombustible materials with negligible (0-0.1) fire propagation index.

Matched MeSH terms: Adenosine Triphosphate
Acetic acid induces pH-independent cellular energy depletion in Salmonella enterica

Tan SM, Lee SM, Dykes GA

Foodborne Pathog Dis, 2015 Mar;12(3):183-9.
PMID: 25562466 DOI: 10.1089/fpd.2014.1853

Weak organic acids are widely used as preservatives and disinfectants in the food industry. Despite their widespread use, the antimicrobial mode of action of organic acids is still not fully understood. This study investigated the effect of acetic acid on the cell membranes and cellular energy generation of four Salmonella strains. Using a nucleic acid/protein assay, it was established that acetic acid did not cause leakage of intracellular components from the strains. A scanning electron microscopy study further confirmed that membrane disruption was not the antimicrobial mode of action of acetic acid. Some elongated Salmonella cells observed in the micrographs indicated a possibility that acetic acid may inhibit DNA synthesis in the bacterial cells. Using an ATP assay, it was found that at a neutral pH, acetic acid caused cellular energy depletion with an ADP/ATP ratio in the range between 0.48 and 2.63 (p<0.05) that was apparent for the four Salmonella strains. We suggest that this effect was probably due solely to the action of undissociated acid molecules. The antimicrobial effect of acetic acid was better under acidic conditions (ADP/ATP ratio of 5.56 ± 1.27; p<0.05), where the role of both pH and undissociated acid molecules can act together. We concluded that the inhibitory effect of acetic acid is not solely attributable to acidic pH but also to undissociated acid molecules. This finding has implication for the use of acetic acid as an antimicrobial against Salmonella on food products, such as chicken meat, which can buffer its pH.

Matched MeSH terms: Adenosine Triphosphate/chemistry
Fulltext Role of Purinergic Signalling in Endothelial Dysfunction and Thrombo-Inflammation in Ischaemic Stroke and Cerebral Small Vessel Disease

Lee NT, Ong LK, Gyawali P, Nassir CMNCM, Mustapha M, Nandurkar HH, et al.

Biomolecules, 2021 07 06;11(7).
PMID: 34356618 DOI: 10.3390/biom11070994

The cerebral endothelium is an active interface between blood and the central nervous system. In addition to being a physical barrier between the blood and the brain, the endothelium also actively regulates metabolic homeostasis, vascular tone and permeability, coagulation, and movement of immune cells. Being part of the blood-brain barrier, endothelial cells of the brain have specialized morphology, physiology, and phenotypes due to their unique microenvironment. Known cardiovascular risk factors facilitate cerebral endothelial dysfunction, leading to impaired vasodilation, an aggravated inflammatory response, as well as increased oxidative stress and vascular proliferation. This culminates in the thrombo-inflammatory response, an underlying cause of ischemic stroke and cerebral small vessel disease (CSVD). These events are further exacerbated when blood flow is returned to the brain after a period of ischemia, a phenomenon termed ischemia-reperfusion injury. Purinergic signaling is an endogenous molecular pathway in which the enzymes CD39 and CD73 catabolize extracellular adenosine triphosphate (eATP) to adenosine. After ischemia and CSVD, eATP is released from dying neurons as a damage molecule, triggering thrombosis and inflammation. In contrast, adenosine is anti-thrombotic, protects against oxidative stress, and suppresses the immune response. Evidently, therapies that promote adenosine generation or boost CD39 activity at the site of endothelial injury have promising benefits in the context of atherothrombotic stroke and can be extended to current CSVD known pathomechanisms. Here, we have reviewed the rationale and benefits of CD39 and CD39 therapies to treat endothelial dysfunction in the brain.

Matched MeSH terms: Adenosine Triphosphate/metabolism*
Cellular and hormonal control in glycogen metabolism--recent advances

Thambyrajah V, Karunairatnam MC

Med J Malaya, 1972 Sep;27(1):33-9.
PMID: 4345646
Matched MeSH terms: Adenosine Triphosphate/metabolism
Fulltext Computational prediction of changes in brain metabolic fluxes during Parkinson's disease from mRNA expression

Supandi F, van Beek JHGM

PLoS One, 2018;13(9):e0203687.
PMID: 30208076 DOI: 10.1371/journal.pone.0203687

BACKGROUND: Parkinson's disease is a widespread neurodegenerative disorder which affects brain metabolism. Although changes in gene expression during disease are often measured, it is difficult to predict metabolic fluxes from gene expression data. Here we explore the hypothesis that changes in gene expression for enzymes tend to parallel flux changes in biochemical reaction pathways in the brain metabolic network. This hypothesis is the basis of a computational method to predict metabolic flux changes from post-mortem gene expression measurements in Parkinson's disease (PD) brain.
RESULTS: We use a network model of central metabolism and optimize the correspondence between relative changes in fluxes and in gene expression. To this end we apply the Least-squares with Equalities and Inequalities algorithm integrated with Flux Balance Analysis (Lsei-FBA). We predict for PD (1) decreases in glycolytic rate and oxygen consumption and an increase in lactate production in brain cortex that correspond with measurements (2) relative flux decreases in ATP synthesis, in the malate-aspartate shuttle and midway in the TCA cycle that are substantially larger than relative changes in glucose uptake in the substantia nigra, dopaminergic neurons and most other brain regions (3) shifts in redox shuttles between cytosol and mitochondria (4) in contrast to Alzheimer's disease: little activation of the gamma-aminobutyric acid shunt pathway in compensation for decreased alpha-ketoglutarate dehydrogenase activity (5) in the globus pallidus internus, metabolic fluxes are increased, reflecting increased functional activity.
CONCLUSION: Our method predicts metabolic changes from gene expression data that correspond in direction and order of magnitude with presently available experimental observations during Parkinson's disease, indicating that the hypothesis may be useful for some biochemical pathways. Lsei-FBA generates predictions of flux distributions in neurons and small brain regions for which accurate metabolic flux measurements are not yet possible.

Matched MeSH terms: Adenosine Triphosphate/metabolism
Insensitivity of bacterial nucleic acid biosyntheses to a morphine-like narcotic

Wolfe AD, Hahn FE

Naturwissenschaften, 1975 Feb;62(2):99.
PMID: 1683
Matched MeSH terms: Adenosine Triphosphate/metabolism
Fulltext ATP-activated P2X7 receptor in the pathophysiology of mood disorders and as an emerging target for the development of novel antidepressant therapeutics

Wei L, Syed Mortadza SA, Yan J, Zhang L, Wang L, Yin Y, et al.

Neurosci Biobehav Rev, 2018 Apr;87:192-205.
PMID: 29453990 DOI: 10.1016/j.neubiorev.2018.02.005

Mood disorders are a group of psychiatric conditions that represent leading global disease burdens. Increasing evidence from clinical and preclinical studies supports that innate immune system dysfunction plays an important part in the pathophysiology of mood disorders. P2X7 receptor, belonging to the ligand-gated ion channel P2X subfamily of purinergic P2 receptors for extracellular ATP, is highly expressed in immune cells including microglia in the central nervous system (CNS) and has a vital role in mediating innate immune response. The P2X7 receptor is also important in neuron-glia signalling in the CNS. The gene encoding human P2X7 receptor is located in a locus of susceptibility to mood disorders. In this review, we will discuss the recent progress in understanding the role of the P2X7 receptor in the pathogenesis and development of mood disorders and in discovering CNS-penetrable P2X7 antagonists for potential uses in in vivo imaging to monitor brain inflammation and antidepressant therapeutics.

Matched MeSH terms: Adenosine Triphosphate/physiology*
Assessing the Performance of a Real-Time Total Adenylate (ATP+ADP+AMP) Detection Assay for Surface Hygiene Monitoring in Food Manufacturing Plants and Commercial Kitchens

Ching CL, Kamaruddin A, Rajangan CS

J Food Prot, 2021 Jun 01;84(6):973-983.
PMID: 33232455 DOI: 10.4315/JFP-20-294

ABSTRACT: Environmental hygiene monitoring in the food processing environment has become important in current food safety programs to ensure safe food production. However, conventional monitoring of surface hygiene based on visual inspection and microbial counts is slow, tedious, and thus unable to support the current risk-based management system. Therefore, this study was conducted to assess the performance of a real-time total adenylate assay that detected ATP+ADP+AMP (A3) for food contact surface hygiene in 13 food processing plants and two commercial kitchens in Malaysia. The A3 value was compared with the microbial count (aerobic plate count [APC]) on food contact surfaces. Receiver-operating characteristic (ROC) analysis was performed to assess the reliability of the data and to determine the optimal threshold value for hygiene indication of food contact surfaces. Overall, the A3 value demonstrated a weak positive relationship with APC. However, the A3 value significantly correlated with APC for food processing environments associated with raw meat and raw food ingredients such as fruit that harbor a high microbial load. ROC analysis suggested an optimal threshold for the A3 value of 500 relative light units to balance the sensitivity and specificity at 0.728 and 0.719, respectively. The A3 assay as a hygiene indicator for food contact surfaces had an efficiency of 72.1%, indicating its reliability as a general hygiene indicator.

Matched MeSH terms: Adenosine Triphosphate/analysis
Therapeutic evaluation and metabolic reprograming of isosteviol sodium in a rat model of ischemic cardiomyopathy

Cao Y, Lu Z, Wang D, Tan KS, Liu W, Wu Q, et al.

Eur J Pharmacol, 2021 Nov 15;911:174539.
PMID: 34599913 DOI: 10.1016/j.ejphar.2021.174539

Ischemia heart disease, one of the lethal cardiovascular diseases, irreversibly impairs cardiac function and is recognized as the primary risk factor for mortality in industrialized countries. The myocardial ischemia treatment still faces a considerable degree of increasing unmet needs. Isosteviol sodium (STVNa) and its derivatives have been proven to effectively alleviate metabolic diseases, hypertension, and heart hypertrophy. Little is known about how STVNa confers the cardioprotective effect during acute myocardial ischemia (AMI). In the present study, a rat model of acute ST-segment-elevation myocardial ischemia by left anterior descending (LAD) ligation was established. Compared to the AMI model group, STVNa administration (4 mg/kg, twice a day) well preserved left ventricle function by ejection fraction (45.10 ± 10.39 vs. 73.64 ± 13.15, p = 0.0013) and fractional shortening (22.94 ± 6.28 vs. 44.00 ± 11.05, p = 0.0017). Further analysis shows that high-dose STVNa (4 mg/kg) significantly improved the hemodynamics in AMI rats, with LVSP (88.25 ± 12.78 vs 99.75 ± 5.10, p = 0.018), max dP/dt (2978.45 ± 832.46 vs 4048.56 ± 827.23, p = 0.096), LVEDP (19.88 ± 2.00 vs 22.26 ± 3.21, p = 0.04) and left ventricular relaxation time constant (Tau) (0.030 ± 0.006 vs 0.021 ± 0.004, p = 0.021). Mechanically, STVNa administration retained the myocardial levels of phosphorylated AMPK, and CPT1b. Moreover, STVNa significantly increased the total energy expenditure, and reduced fatty acid accumulation through mitochondrial oxidative phosphorylation, which was supported by the indirect calorimetry and cellular energy analysis. Taken together, these findings suggest that STVNa is a potential cardioprotection agent for ischemic cardiomyopathy, likely through improving energy homeostasis, left ventricular hemodynamics, and heart function.

Matched MeSH terms: Adenosine Triphosphate/biosynthesis
Enhanced mitochondrial function and delivery from adipose-derived stem cell spheres via the EZH2-H3K27me3-PPARγ pathway for advanced therapy

Chang MM, Chu DT, Lin SC, Lee JS, Vu TD, Vu HT, et al.

Stem Cell Res Ther, 2025 Mar 11;16(1):129.
PMID: 40069892 DOI: 10.1186/s13287-025-04164-1

BACKGROUND: Microenvironmental alterations induce significant genetic and epigenetic changes in stem cells. Mitochondria, essential for regenerative capabilities, provide the necessary energy for stem cell function. However, the specific roles of histone modifications and mitochondrial dynamics in human adipose-derived stem cells (ASCs) during morphological transformations remain poorly understood. In this study, we aim to elucidate the mechanisms by which ASC sphere formation enhances mitochondrial function, delivery, and rescue efficiency.
METHODS: ASCs were cultured on chitosan nano-deposited surfaces to form 3D spheres. Mitochondrial activity and ATP production were assessed using MitoTracker staining, Seahorse XF analysis, and ATP luminescence assays. Single-cell RNA sequencing, followed by Ingenuity Pathway Analysis (IPA), was conducted to uncover key regulatory pathways, which were validated through molecular techniques. Pathway involvement was confirmed using epigenetic inhibitors or PPARγ-modulating drugs. Mitochondrial structural integrity and delivery efficiency were evaluated after isolation.
RESULTS: Chitosan-induced ASC spheres exhibited unique compact mitochondrial morphology, characterized by condensed cristae, enhanced mitochondrial activity, and increased ATP production through oxidative phosphorylation. High expressions of mitochondrial complex I genes and elevated levels of mitochondrial complex proteins were observed without an increase in reactive oxygen species (ROS). Epigenetic modification of H3K27me3 and PPARγ involvement were discovered and confirmed by inhibiting H3K27me3 with the specific EZH2 inhibitor GSK126 and by adding the PPARγ agonist Rosiglitazone (RSG). Isolated mitochondria from ASC spheres showed improved structural stability and delivery efficiency, suppressed the of inflammatory cytokines in LPS- and TNFα-induced inflamed cells, and rescued cells from damage, thereby enhancing function and promoting recovery.
CONCLUSION: Enhancing mitochondrial ATP production via the EZH2-H3K27me3-PPARγ pathway offers an alternative strategy to conventional cell-based therapies. High-functional mitochondria and delivery efficiency show significant potential for regenerative medicine applications.

Matched MeSH terms: Adenosine Triphosphate/metabolism
Biophysical changes of ATP binding pocket may explain loss of kinase activity in mutant DAPK3 in cancer: A molecular dynamic simulation analysis

Agarwal T, Annamalai N, Maiti TK, Arsad H

Gene, 2016 Apr 10;580(1):17-25.
PMID: 26748242 DOI: 10.1016/j.gene.2015.12.066

DAPK3 belongs to family of DAPK (death-associated protein kinases) and is involved in the regulation of progression of the cell cycle, cell proliferation, apoptosis and autophagy. It is considered as a tumor suppressor kinase, suggesting the loss of its function in case of certain specific mutations. The T112M, D161N and P216S mutations in DAPK3 have been observed in cancer patients. These DAPK3 mutants have been associated with very low kinase activity, which results in the cellular progression towards cancer. However, a clear understanding of the structural and biophysical variations that occur in DAPK3 with these mutations, resulting in the decreased kinase activity has yet not been deciphered. We performed a molecular dynamic simulation study to investigate such structural variations. Our results revealed that mutations caused a significant structural variation in DAPK3, majorly concentrated in the flexible loops that form part of the ATP binding pocket. Interestingly, D161N and P216S mutations collapsed the ATP binding pocket through flexible loops invasion, hindering ATP binding which resulted in very low kinase activity. On the contrary, T112M mutant DAPK3 reduces ATP binding potential through outward distortion of flexible loops. In addition, the mutant lacked characteristic features of the active protein kinase including proper interaction between HR/FD and DFG motifs, well structured hydrophobic spine and Lys42-Glu64 salt bridge interaction. These observations could possibly explain the underlying mechanism associated with the loss of kinase activity with T112M, D161N and P216S mutation in DAPK3.

Matched MeSH terms: Adenosine Triphosphate
Design, Synthesis and Biological Potential of 5-(2-Amino-6-(3/4-bromophenyl)pyrimidin-4-yl)benzene-1,3-diol Scaffolds as Promising Antimicrobial and Anticancer Agents

Kumar S, Narasimhan B, Lim SM, Ramasamy K, Mani V, Shah SAA

Mini Rev Med Chem, 2019;19(10):851-864.
PMID: 30306864 DOI: 10.2174/1389557518666181009141924

BACKGROUND: A series of 5-(2-amino-6-(3/4-bromophenyl)pyrimidin-4-yl)benzene-1,3-diol scaffolds was synthesized by Claisen-Schmidt condensation and characterized by NMR, IR, Mass and elemental analyses.
METHODS: The synthesized pyrimidine scaffolds were screened for their antimicrobial activity by tube dilution method as well for antiproliferative activity (human colorectal (HCT116) cancer cell line) by SRB assay.
RESULTS: The antimicrobial screening results demonstrated that compounds, k6, k12, k14 and k20 were found to be the most potent ones against selected microbial species. The anticancer screening results indicated that compounds, k8 and k14 displayed potent anticancer activity against cancer cell line (HCT116).
CONCLUSION: Further, the molecular docking study carried to find out the interaction between active pyrimidine compounds with CDK-8 protein indicated that compound k14 showed best dock score with better potency within the ATP binding pocket and may be used as a lead for rational drug designing of the anticancer molecule.

Matched MeSH terms: Adenosine Triphosphate
Fulltext Calpain Inhibition Restores Autophagy and Prevents Mitochondrial Fragmentation in a Human iPSC Model of Diabetic Endotheliopathy

Ong SB, Lee WH, Shao NY, Ismail NI, Katwadi K, Lim MM, et al.

Stem Cell Reports, 2019 03 05;12(3):597-610.
PMID: 30799273 DOI: 10.1016/j.stemcr.2019.01.017

The relationship between diabetes and endothelial dysfunction remains unclear, particularly the association with pathological activation of calpain, an intracellular cysteine protease. Here, we used human induced pluripotent stem cells-derived endothelial cells (iPSC-ECs) to investigate the effects of diabetes on vascular health. Our results indicate that iPSC-ECs exposed to hyperglycemia had impaired autophagy, increased mitochondria fragmentation, and was associated with increased calpain activity. In addition, hyperglycemic iPSC-ECs had increased susceptibility to cell death when subjected to a secondary insult-simulated ischemia-reperfusion injury (sIRI). Importantly, calpain inhibition restored autophagy and reduced mitochondrial fragmentation, concurrent with maintenance of ATP production, normalized reactive oxygen species levels and reduced susceptibility to sIRI. Using a human iPSC model of diabetic endotheliopathy, we demonstrated that restoration of autophagy and prevention of mitochondrial fragmentation via calpain inhibition improves vascular integrity. Our human iPSC-EC model thus represents a valuable platform to explore biological mechanisms and new treatments for diabetes-induced endothelial dysfunction.

Matched MeSH terms: Adenosine Triphosphate
Fulltext Polymethoxyflavones fromNicotiana plumbaginifolia(Solanaceae) Exert Antinociceptive and Neuropharmacological Effects in Mice

Shajib MS, Rashid RB, Ming LC, Islam S, Sarker MMR, Nahar L, et al.

Front Pharmacol, 2018;9:85.
PMID: 29515437 DOI: 10.3389/fphar.2018.00085

Polymethoxylavones (PMFs) are known to exhibit significant anti-inflammatory and neuroprotective properties.Nicotiana plumbaginifolia, an annual Bangladeshi herb, is rich in polymethoxyflavones that possess significant analgesic and anxiolytic activities. The present study aimed to determine the antinociceptive and neuropharmacological activities of polyoxygenated flavonoids namely- 3,3',5,6,7,8-hexamethoxy-4',5'-methylenedioxyflavone (1), 3,3',4',5',5,6,7,8-octamethoxyflavone (exoticin) (2), 6,7,4',5'-dimethylenedioxy-3,5,3'-trimethoxyflavone (3), and 3,3',4',5,5',8-hexamethoxy-6,7-methylenedioxyflavone (4), isolated and identified fromN. plumbaginifolia. Antinociceptive activity was assessed using the acetic-acid induced writhing, hot plate, tail immersion, formalin and carrageenan-induced paw edema tests, whereas neuropharmacological effects were evaluated in the hole cross, open field and elevated plus maze test. Oral treatment of compounds1,3, and4(12.5-25 mg/kg b.w.) exhibited dose-dependent and significant (p< 0.01) antinociceptive activity in the acetic-acid, formalin, carrageenan, and thermal (hot plate)-induced pain models. The association of ATP-sensitive K+channel and opioid systems in their antinociceptive effect was obvious from the antagonist effect of glibenclamide and naloxone, respectively. These findings suggested central and peripheral antinociceptive activities of the compounds. Compound1,3, and4(12.5 mg/kg b.w.) demonstrated significant (p< 0.05) anxiolytic-like activity in the elevated plus-maze test, while the involvement of GABAAreceptor in the action of compound3and4was evident from the reversal effects of flumazenil. In addition, compounds1and4(12.5-25 mg/kg b.w) exhibited anxiolytic activity without altering the locomotor responses. The present study suggested that the polymethoxyflavones (1-4) fromN. Plumbaginifoliacould be considered as suitable candidates for the development of analgesic and anxiolytic agents.

Matched MeSH terms: Adenosine Triphosphate

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